Caspases are a highly conserved family of cysteine-aspartyl endoproteases known for their essential roles in regulating apoptosis, inflammation, cell differentiation, and proliferation. Aside from the canonical roles in apoptosis, their functions in diverse cell functions and diseases, including neurodegenerative disease, autoimmune disorders, and cancers, remain poorly defined. Studying caspases is very difficult as they have complex activation mechanisms. Most caspases exist as inactive proenzymes. There are multiple caspase isoforms, some of which have redundant functions. Additionally, they behave differently in living cells and tissues, rendering in vitro assays ineffective, and are involved in crosstalk with other cellular processes such as autophagy and immune responses. Due to these challenges, new approaches can elucidate the biological function of specific caspases. Complementary to genetic approaches, small molecule inhibitors have emerged as useful tools for modulating caspase activity. However, achieving high selectivity remains a central challenge for caspase-directed inhibitor development efforts due to all twelve human caspases' high sequence and structure homology. Here, using a chemoproteomics and high-throughput screening (HTS) approach, I identified lead compounds that selectively label and inhibit procaspase-2 and identified new pan-caspase reactive inhibitors. First, using a chemical-proteomic platform termed isoTOP-ABPP, I identified a highly reactive non-catalytic cysteine residue, C370, located near the active site of caspase-2. I assayed a panel of cysteine reactive electrophiles using an engineered TEV-cleavable caspase-2 construct to validate the hits against pro-caspase-2 activity. I found a selective pro-caspase-2 inhibitor that targets the non-catalytic cysteine residue and binds the monomeric form of the enzyme. I also confirmed target engagement using cellular thermal shift assays (CETSA). Next, I identified a group of caspase inhibitors using a high-throughput screening assay. From a screen of approximately 120,000 compounds, I found pifithrin-µ (PFTµ), a known p53 inhibitor, as a caspase reactive covalent inhibitor and interesting scaffold molecule. From that same group of compounds, I found that the decomposed product of compound SO265 was driving caspase inhibition in my initial screen. Target engagement was also confirmed for both compounds using CETSA. I found that PFTµ and the other pan-caspase reactive electrophiles could protect Jurkat cells from Fas ligand and staurosporine-mediated apoptosis. This study demonstrates the potential of chemoproteomics and high-throughput approaches to help identify selective caspase inhibitors.